Exploiting an Allosteric Binding Site of PRMT3 Yields Potent and Selective Inhibitors

Liu, Feng; Li, Fengling; Ma, Anqi; Dobrovetsky, E.; Dong, Aiping; Gao, Canzhu; Korboukh, Ilia; Liu, Jing; Smil, D.; Brown, Peter J.; Frye, Stephen V.; Arrowsmith, C.H.; Schapira, Matthieu; Vedadi, Masoud; Jin, Jian

doi:10.1021/jm3018332

Cited by 63 publications

(61 citation statements)

References 67 publications

(173 reference statements)

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“…[11] We later reported structure-activity rela-tionship studies of this inhibitor, leading to the iden-tification of a sub-micromolar PRMT3 inhibitor. [12] To discover the first chemical probe of PRMT3, we further optimized both the left-hand side (LHS) and right-hand side (RHS) moieties of this scaffold through structure-guided design and synthesis. In particular, we conducted a scaffold hopping exercise (see the Sup-porting Information (SI) for details) for replacing the LHS benzothiadiazole moiety, which resulted in the selection of several replacement candidates, including an isoquinoline moiety.…”

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confidence: 99%

“…We attribute the increased potency of SGC707 over parent compounds to the presence of the isoquinoline ring that optimally occupies the PRMT3 cavity, and the pyrrolidine amide that could form direct or watermediated contacts with the side chain of K392. [12] Our inactive control XY1, which contains a naphthyl group replacing the isoquinoline group, lacks the key hydrogen bond with T466. This hydrogen bond is absolutely desolvated, thus contributing strongly to the PRMT3-SGC707 interaction.…”

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confidence: 99%

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A Potent, Selective and Cell‐Active Allosteric Inhibitor of Protein Arginine Methyltransferase 3 (PRMT3)

Kanıskan

Szewczyk

et al. 2015

Angewandte Chemie

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] These authors contributed equally to this work.Supporting information for this article (including detailed synthetic procedures and compound characterization as well as methods for scaffold hopping, crystallization, structure determination, bio-chemical assays, SPR, ITC, PRMT3 InCELL Hunter assay, cellular PRMT3 assay, cell viability assay, and mouse PK studies) is available on the WWW under http://dx

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confidence: 99%

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confidence: 99%

A Potent, Selective and Cell‐Active Allosteric Inhibitor of Protein Arginine Methyltransferase 3 (PRMT3)

Kanıskan

Szewczyk

et al. 2015

Angewandte Chemie

Self Cite

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“…The SGC has enabled the public dissemination of a substantial number of epigenetic protein crystal structures (helpful for computational approaches in medicinal chemistry) and chemical probes, e.g., G9a/GLP (20), EZH2 (21), DOT1L (22), L3MBTL3 (23), BET (24,25), and PRMT3 (ref. 26 and Figure 2).…”

Section: Challenges To Epigenetic Drug Discoverymentioning

confidence: 94%

Cancer epigenetics drug discovery and development: the challenge of hitting the mark

Campbell¹,

Tummino²

2014

J. Clin. Invest.

134

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Over the past several years, there has been rapidly expanding evidence of epigenetic dysregulation in cancer, in which histone and DNA modification play a critical role in tumor growth and survival. These findings have gained the attention of the drug discovery and development community, and offer the potential for a second generation of cancer epigenetic agents for patients following the approved "first generation" of DNA methylation (e.g., Dacogen, Vidaza) and broad-spectrum HDAC inhibitors (e.g., Vorinostat, Romidepsin). This Review provides an analysis of prospects for discovery and development of novel cancer agents that target epigenetic proteins. We will examine key examples of epigenetic dysregulation in tumors as well as challenges to epigenetic drug discovery with emerging biology and novel classes of drug targets. We will also highlight recent successes in cancer epigenetics drug discovery and consider important factors for clinical success in this burgeoning area. Epigenetic dysregulation in cancerEpigenetic information is contained in the cell in multiple forms that include DNA methylation, histone modification (methylation, acetylation, phosphorylation, etc.), nucleosome positioning, and microRNA expression, among others. This combined information constitutes the epigenome. A comprehensive understanding of epigenomic dysregulation in specific cancer types has not been elucidated yet. Currently, there is an understanding of tumor-specific types of epigenetic modifications without a full appreciation of the context of the entire cancer epigenome in the specific tumor.Cancer epigenetic dysregulation can be categorized into three types: (a) altered DNA or histone modification, (b) somatic alteration in an epigenetic protein, and (c) altered expression of an epigenetic protein. Those types of cancer epigenome dysregulation have been reviewed comprehensively elsewhere (1-3), and only will be referred to here.The primary types of epigenetic modification that have been targeted by drug discovery efforts in recent years are histone methylation and acetylation. The enzymes that catalyze these histone post-translational modifications, which include histone methyltransferases, histone demethylases, histone acetyltransferases, and histone deacetylases, are considered potentially tractable targets for pharmacological intervention. Stated differently, drug discovery scientists believe that it may be possible to discover and optimize inhibitors to these activated enzyme targets as a direct means of pharmacological targeting of epigenetic dysregulation.Of the three types of epigenetic dysregulation described above, a higher priority is placed on tumor somatic alterations in epigenetic proteins. There is a higher probability that somatic alterations will be consistent between cultured cancer cells and patient tumor samples as compared to protein expression, histone or DNA modification, since there is some evidence that the latter is different in cell culture (4, 5). Hence, a somatic alteration in a histone-modifying...

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“…Prior to quantitation by autoradiography or liquid scintillation counting, the methylated substrates have to be separated from unreacted SAM by using different approaches such as polyacrylamide gel electrophoresis (radiometric gel assay, RGA) [70–76], pipette chromatography (ZipTip assay) [77], and filtering on glass fiber or phosphocellulose paper discs (radiometric filter assay, RFA) [37, 73, 78–90]. To eliminate the washing step required for the above described radiometric assays, scintillation proximity assay (SPA) has been implemented [80, 91–101], in which the scintillation signals depend on the micrometer proximity between biotinylated substrates and streptavidin-coated scintillants (either FlashPlates or streptavidin-coated microscopic beads). As such, the SAM molecules present in the bulk solution fall off the SPA distance and thus do not produce scintillation signals.…”

Section: Biochemical Assays In Prmt Inhibitor Studymentioning

confidence: 99%

Small Molecule Inhibitors of Protein Arginine Methyltransferases

Qian

et al. 2016

Expert Opinion on Investigational Drugs

106

115

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Introduction Arginine methylation is an abundant posttranslational modification occurring in mammalian cells and catalyzed by protein arginine methyltransferases (PRMTs). Misregulation and aberrant expression of PRMTs are associated with various disease states, notably cancer. PRMTs are prominent therapeutic targets in drug discovery. Areas covered The authors provide an updated review of the research on the development of chemical modulators for PRMTs. Great efforts are seen in screening and designing potent and selective PRMT inhibitors, and a number of micromolar and submicromolar inhibitors have been obtained for key PRMT enzymes such as PRMT1, CARM1, and PRMT5. The authors provide a focus on their chemical structures, mechanism of action, and pharmacological activities. Pros and cons of each type of inhibitors are also discussed. Expert opinion Several key challenging issues exist in PRMT inhibitor discovery. Structural mechanisms of many PRMT inhibitors remain unclear. There lacks consistency in potency data due to divergence of assay methods and conditions. Physiologically relevant cellular assays are warranted. Substantial engagements are needed to investigate pharmacodynamics and pharmacokinetics of the new PRMT inhibitors in pertinent disease models. Discovery and evaluation of potent, isoform-selective, cell-permeable and in vivo-active PRMT modulators will continue to be an active arena of research in years ahead.

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Exploiting an Allosteric Binding Site of PRMT3 Yields Potent and Selective Inhibitors

Cited by 63 publications

References 67 publications

A Potent, Selective and Cell‐Active Allosteric Inhibitor of Protein Arginine Methyltransferase 3 (PRMT3)

A Potent, Selective and Cell‐Active Allosteric Inhibitor of Protein Arginine Methyltransferase 3 (PRMT3)

Cancer epigenetics drug discovery and development: the challenge of hitting the mark

Small Molecule Inhibitors of Protein Arginine Methyltransferases

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